A systematic review and meta-analysis of short-stay programmes for total hip and knee replacement, focusing on safety and optimal patient selection

Background Short-stay joint replacement programmes are used in many countries but there has been little scrutiny of safety outcomes in the literature. We aimed to systematically review evidence on the safety of short-stay programmes versus usual care for total hip (THR) and knee replacement (KR), and optimal patient selection. Methods A systematic review and meta-analysis. Randomised controlled trials (RCTs) and quasi-experimental studies including a comparator group reporting on 14 safety outcomes (hospital readmissions, reoperations, blood loss, emergency department visits, infection, mortality, neurovascular injury, other complications, periprosthetic fractures, postoperative falls, venous thromboembolism, wound complications, dislocation, stiffness) within 90 days postoperatively in adults ≥ 18 years undergoing primary THR or KR were included. Secondary outcomes were associations between patient demographics or clinical characteristics and patient outcomes. Four databases were searched between January 2000 and May 2023. Risk of bias and certainty of the evidence were assessed. Results Forty-nine studies were included. Based upon low certainty RCT evidence, short-stay programmes may not reduce readmission (OR 0.95, 95% CI 0.12–7.43); blood transfusion requirements (OR 1.75, 95% CI 0.27–11.36); neurovascular injury (OR 0.31, 95% CI 0.01–7.92); other complications (OR 0.63, 95% CI 0.26–1.53); or stiffness (OR 1.04, 95% CI 0.53–2.05). For registry studies, there was no difference in readmission, infection, neurovascular injury, other complications, venous thromboembolism, or wound complications but there were reductions in mortality and dislocations. For interrupted time series studies, there was no difference in readmissions, reoperations, blood loss volume, emergency department visits, infection, mortality, or neurovascular injury; reduced odds of blood transfusion and other complications, but increased odds of periprosthetic fracture. For other observational studies, there was an increased risk of readmission, no difference in blood loss volume, infection, other complications, or wound complications, reduced odds of requiring blood transfusion, reduced mortality, and reduced venous thromboembolism. One study examined an outcome relevant to optimal patient selection; it reported comparable blood loss for short-stay male and female participants (p = 0.814). Conclusions There is low certainty evidence that short-stay programmes for THR and KR may have non-inferior 90-day safety outcomes. There is little evidence on factors informing optimal patient selection; this remains an important knowledge gap. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-023-03219-5.


Background
The demand for total hip (THR) and knee replacement (KR) surgeries is increasing with the growing burden of osteoarthritis [1][2][3].Between 2009 and 2019, the average rate of THR and KR increased by 22 and 35%, respectively, across all Organisation for Economic Co-operation and Development (OECD) countries [4].The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) [5] and the United Kingdom (UK) National Joint Registry [6] have each reported that delays in accessing joint replacement surgery, combined with anticipated growing demand, need to be addressed.
The capacity to meet expected joint replacement demand requires safe and efficient models of care.Shortstay programmes (also known as 'fast track' , 'enhanced recovery after surgery' or 'rapid recovery' programmes) are those which seek to reduce acute hospital length of stay after elective primary THR or KR surgery [7].Shortstay programmes utilise a clinical pathway that enhances functional recovery and facilitates earlier patient discharge.Features of these programmes may include (but are not limited to) pre-operative education, standardised anaesthetic protocol and/or utilisation of local anaesthesia, postoperative nausea prophylaxis, blood conservation measures and multimodal analgesia [8][9][10].
Short-stay programmes have been successfully implemented in the United States (US) and some European countries [11,12] yet they remain underutilised in Australia [9,13].Systematic reviews have found that short-stay programmes for THR and KR are associated with reduced healthcare and patient costs [14], yet few controlled trials have been conducted on their safety.Reviews of short-stay programmes have thus far focused on a limited set of safety outcomes compared to usual care: one review reported fewer complications with short-stay programmes [15], and another found no effect on complications or hospital readmission [8].Factors associated with poorer patient outcomes have not been systematically examined, yet this information is essential for guiding appropriate patient selection.Establishing the safety profile of short-stay programmes, and factors associated with suboptimal outcomes could inform future efforts to develop, implement and scale-up short-stay joint replacement programmes in Australia and other countries where these are not commonly used.
This study aimed to systematically review the evidence on the safety of short-stay THR and KR programmes, compared with usual care, and patient factors associated with poor outcomes.

Design
This study is a systematic review.The protocol was registered on the PROSPERO International Prospective Register of Systematic Reviews (registration number 351026) and is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement (Supplementary File 1) [16].The second component of the registered review protocol (comprising a review of qualitative studies examining barriers and enablers to the implementation and sustainability of short-stay joint replacement programmes) will be reported separately.

Eligibility criteria
We included randomised controlled trials (RCTs) as well as registry, interrupted time series, and other observational studies.The studies could have been conducted in any setting that compared a short-stay programme for adults aged ≥ 18 years undergoing unilateral or bilateral, total or uni-compartmental KR or THR, included a usual care (traditional or standard care) comparator group, and reported safety outcomes within 90 days post-operatively, and/or associations between patient demographics and/ or clinical characteristics and patient outcomes.Shortstay programmes were those that specifically identified as being 'short-stay' , 'enhanced recovery after surgery' , 'enhanced recovery' , 'fast-track' , 'accelerated discharge' , 'early discharge' or 'rapid recovery' programmes or models of care.A standardised definition of a short-stay programme was not adopted as such programmes are not delivered consistently across hospital settings or countries, and length of stay targets are variable.There was no study size restriction, but we excluded studies not published in English.
Exclusions were studies that only compared the partial implementation of a short-stay programme (representing the use of short-stay programme components rather than a usual care comparator) with full implementation of the programme, reviews, conference publications, case studies and grey literature.Studies reporting solely on joint replacement for traumatic injury (including traumatic fracture) or malignancy, or studies reporting solely on revision joint replacement were also excluded.Where studies involved mixed cohorts of patients, these were only eligible for inclusion if data for patients undergoing primary elective joint replacement were reported separately.Studies that focused on same-day discharge or outpatient joint replacement programmes were excluded as these patient populations are highly selected (these programmes are appropriate for a relatively small proportion of patients, based on clinical, social and home environment factors) and these types of programmes do not feature prominently in the Australian healthcare system.

Outcomes
Safety outcomes and patient-related outcomes were selected based on discussions with the multidisciplinary research team, which comprised expertise in orthopaedic surgery, rheumatology, public health, physiotherapy, health economics and consumer-led research.
Six patient-related outcomes were considered in relation to patient demographics or clinical characteristics: (1) activities of daily living, including ambulation and mobility, (2) functional outcomes, (3) joint-specific patient-reported outcome measures (PROMs), (4) pain at rest or during activity, (5) patient satisfaction and (6) quality of life.

Search strategy and identification and selection of included papers
An electronic literature search was undertaken in Medline (OVID), Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE and the Cochrane Central Register of Controlled Trials (CEN-TRAL).A comprehensive search strategy was designed using relevant search terms (Supplementary File 2).The reference lists of the included studies were hand searched to identify any additional primary studies.The search strategy was limited to articles published between 2000 and August 2022.We ran an updated search from 2022 to May 2023 before finalising the review for publication.We also searched ClinicalTrials.gov to identify current research and any published results on short-stay THR or KR programmes [17].
The retrieved articles were loaded into Covidence software (Veritas Health Innovation Ltd, Melbourne, Australia).Two review authors (IA, PV) independently screened the titles and abstracts of all retrieved studies to determine eligibility.The full texts of all potentially eligible studies were reviewed independently by the same two review authors to determine final inclusion.At each review stage, discordance regarding eligibility was discussed and resolved through consensus.Where agreement could not be reached, a third reviewer (RB) was consulted.

Assessment of risk of bias
The risk of bias was assessed independently by two reviewers (IA, DB) using validated critical appraisal tools from the Joanna Briggs Institute (JBI).The JBI critical appraisal tools included nine items for quasiexperimental studies, and 13 items for RCTs [18].The following domains were assessed for RCTs and each potential source of bias was judged as low risk or high risk based on yes/no/unclear (yes low risk, no and unclear high risk) responses to the items: selection and allocation, administration of intervention/exposure, assessment, detection and measurement of the outcome, participant retention and statistical conclusion validity [19].The following domains were assessed for the quasi-experimental studies and each potential source of bias was judged using the same methods: the temporal relationship of the variables (whether it is clear that the intervention precedes the outcome), selection bias, control group, multiple measurements of the outcome, loss to follow-up and statistical conclusion validity [20].

Data extraction and management
One review author (DB) independently extracted data from the included studies using a customised spreadsheet.A second author (IA) independently extracted a random 10% sample of these data to check for consistency.Data extracted included the study design, country, surgical procedure, gender, age, intervention components (mapped to the Consensus statement for perioperative care in THR and KR: Enhanced Recovery After Surgery (ERAS ® ) Society recommendations) [21], and relevant outcomes concerning the safety profile and associations between patient factors and surgical outcomes.For studies that contained more than one short-stay group (for example, partial implementation of short-stay components, full implementation of short-stay components and a usual care group), only the data for the full implementation group was extracted and compared with the usual care group.

Data analysis
Study characteristics and demographic data were reported using means (standard deviation (SD)), medians (interquartile range (IQR)) or frequencies as appropriate.Any data on associations between patient factors and outcomes were reported as published, without further analysis.The diversity of included studies was assessed in terms of study design, interventions and outcomes to determine whether a meta-analysis was appropriate.When pooling was appropriate, data were combined according to study design to examine outcomes based on the level of evidence.Between-study variability was assessed using the I 2 statistic.The I 2 values were interpreted based on the Cochrane Handbook for Systematic Reviews of Interventions (0-40% may be important, 30-60% moderate, 50-90% substantial, > 75% considerable) [22].Where both adjusted and unadjusted effect estimates were reported, we used the unadjusted estimate for meta-analysis.
Where meta-analysis was not possible due to significant diversity of outcome measures or only one study reporting a particular outcome, relevant outcome data were extracted and reported as published.Safety outcomes for THR and KR were combined for meta-analysis except for dislocation (relevant only for THR) and stiffness and/or manipulation (relevant only for KR).
For the number of events or binary outcomes, a random effects model was used and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.The Mantel-Haenszel method was used to weight each estimate.For continuous outcomes, a random effects model was used and the mean difference with 95% confidence intervals was calculated.The generic inverse variance method was used to weight each estimate.A random effects model was chosen to allow for observed differences in study results that may be due to a combination of chance and some genuine variation in the intervention effects [22].All analyses were conducted using Review Manager, V.5.4 (Revman, The Cochrane Collaboration; Oxford, UK).

Grading the certainty of evidence
The certainty of the evidence was assessed separately for the RCTs, followed by the registry, interrupted time series and other observational studies by two reviewers (DB, IA).The certainty of the RCT evidence was assessed using the five GRADE considerations (risk of bias, consistency of effect, indirectness, imprecision and publication bias).The methods described in the Cochrane Handbook for Systematic Reviews of Interventions were followed [23].In accordance with the GRADE handbook, quasi-experimental studies (registry, interrupted time series and other observational studies) were initially graded as low certainty evidence and downgraded for imprecision, indirectness, inconsistency or publication bias, or upgraded if a large magnitude of effect or doseresponse gradient was found [24].The summary of findings table is presented for the RCTs only.

Results
Figure 1 summarises the search and screening processes.The electronic search (2000-August 2022) identified 5411 studies for potential inclusion.After duplicates were removed, 4872 titles and abstracts were screened, 101 full-text articles were screened and overall 46 studies were included.The search was updated (2022-May 2023).An additional 776 studies were identified for potential inclusion; after duplicates were removed, 602 titles and abstracts were screened, seven full-text articles were screened and overall three studies were included.We also identified four trials published on ClinicalTrials.gov; none have published results thus far.

Randomised controlled trials
Risk of bias results for the RCTs can be found in Supplementary File 3.All three trials were at low risk of selection bias but they were all at high risk of performance and detection bias as allocation to treatment groups was not concealed and neither participants nor the treating surgeons were blinded.One trial blinded the surgeon responsible for discharging participants [61], one blinded the physiotherapist responsible for collecting patientreported outcome data (this occurred at 6 months and was not included in our review) [33], and one did not attempt to blind staff [57].Two studies were at low risk of assessment bias [33,61], but one was at high risk based on unclear information on participants lost to follow-up [57].There were few losses to follow-up, reflecting a low risk of attrition bias.Appropriate statistical analysis was used in all trials.

Effects of interventions
The safety outcomes included in each study can be found in Table 3.

RCT evidence
Data from the RCTs were available for only five of the pre-specified 14 safety outcomes: readmissions [33,61], blood loss (including requiring blood transfusion) [61], other complications [33,57,61], neurovascular injury [57], and stiffness and/or manipulation [33,57].Table 4 displays the GRADE results, Supplementary File 4 displays the forest plots, and Supplementary File 5 summarises reported outcome data that were not able to be included in pooled analyses.
Readmissions There was low certainty evidence that short-stay programmes may not reduce the odds of hospital readmission compared to usual care (short-stay: 2/48 [4.2%], usual care: 2/50 [4.0%], OR 0.95, 95% CI 0.12 to 7.46; two trials, 98 participants).The certainty of evidence was downgraded for imprecision due to the small number of studies and events.

Blood transfusion
Compared with usual care, there was low certainty evidence that short-stay programmes may not reduce blood transfusion requirements (short-stay: 3/27 [11.1%], usual care: 2/30 [6.7%], OR 1.75, 95% CI 0.27 to 11.36; one trial, 57 participants).The certainty of evidence was downgraded for imprecision due to the very low event rate from a single study.There was less postoperative bleeding in the short-stay group (average 234.1 ml), compared to usual care (average 387.9 ml), but post-operative haemoglobin levels were similar (shortstay average 6.94, usual care average 6.94).
Neurovascular injury There was low certainty evidence that short-stay programmes may not reduce the odds of neurovascular injury, compared to usual care (short-stay: 0/25 [0%], usual care: 1/24 [4.2%]; OR 0.31, 95% CI 0.01 to 7.92; one trial, 49 participants [57]).The certainty of the evidence was downgraded for imprecision due to the very low event rate from a single study.
Other complications There was low certainty evidence that short-stay programmes may not reduce the odds of experiencing other complications, compared to usual care (short-stay: 11/73 [15.1%], usual care: 17/74 [23.0%];OR 0.63, 95% CI 0.26 to 1.53; three trials, 147 participants, I 2 = 0%).The certainty of the evidence was downgraded for imprecision due to the small number of studies and events.Stiffness and/or manipulation There was low certainty evidence that short-stay programmes may not reduce the odds of stiffness and/or requiring manipulation compared to usual care (short-stay: 2/46 [4.3%], usual care: 1/44 [2.3%]; OR 1.04, 95% CI 0.53 to 2.05; two trials, 90 participants, I 2 = 0%).The certainty of evidence was downgraded for imprecision due to the small number of studies and events.

Registry evidence
Data from the registries were available for nine of the prespecified 14 safety outcomes: readmissions [65], infection [65], mortality [64,65], neurovascular injury [65], other complications [65], venous thromboembolism [65], wound complications [65], dislocation [65], and stiffness and/or manipulation [65].The certainty of the evidence was low.The evidence was not downgraded (there was no serious imprecision, no serious indirectness as the variability likely reflects what happens in practice, no inconsistency, and little evidence of publication bias) or upgraded (no large magnitude of effect and no evidence of a large dose-response gradient).Supplementary File 4 displays the forest plots and Supplementary File 5 summarises reported outcome data that were not able to be included in pooled analyses.
No registry studies assessed reoperations, blood loss (including requiring a blood transfusion), emergency department visits, periprosthetic fractures or postoperative falls.
The certainty of the evidence was low and not downgraded or upgraded.Supplementary File 4 displays the forest plots, and Supplementary File 5 summarises reported outcome data that were not able to be included in pooled analyses.
Readmissions There was low certainty evidence that short-stay programmes may not reduce the odds of hospital readmissions, compared to usual care (short-stay: 443/12,571 [3.5%], usual care: 552/13,322 [4.1%]; OR 0.86, 95% CI 0.72 to 1.03; 21 studies; 25,893 participants; I 2 = 18%).There was no significant difference in the percentage of readmissions from short-stay and usual care participants [55] and no significant difference in readmissions between short-stay and usual care groups at 30 and 90 days [70].
Mortality There was low certainty evidence that shortstay programmes may not reduce the odds of mortality, compared to usual care (short-stay: 31/10,936 [0.28%], usual care: 77/9353 [0.82%]; OR 0.42, 95% CI 0.13, 1.35; 9 studies; 20,289 participants; I 2 = 74%).Survival probability at 1 and 3 months was reported to be the same between short-stay and usual care participants [34] and the percentage of deaths was 0.1% for both groups in a separate study [54].
Other complications There was low certainty evidence that short-stay programmes may reduce the odds of other complications, compared to usual care (short-stay: ).Two studies reported the percentage of other complications in the short-stay and usual care groups [55,58] and one found a significantly reduced number of complications in the short-stay group [58].Two studies reported the number of complications in the short-stay group only [25,60].
Periprosthetic fracture There was low certainty evidence that short-stay programmes may increase the odds of periprosthetic fracture, compared to usual care (short-stay: Postoperative falls Postoperative falls was the only prespecified safety outcome that was unable to be pooled for analysis.One study reported on postoperative falls; it found one participant in the short-stay group had an accidental fall 13 days postoperatively and no falls were reported in the usual care group [45]. Venous thromboembolism There was low certainty evidence that short-stay programmes may reduce the odds of venous thromboembolism, compared to usual care (shortstay: 87/9275 [0.9%], usual care: 148/9549 [1.5%]; OR 0.72, 95% CI 0.55 to 0.95; 9 studies 18,824 participants; I 2 = 0%).
Wound complications There was low certainty evidence that short-stay programmes may not reduce the odds of
Readmissions There was low certainty evidence that short-stay programmes may increase the odds of hospital  [72] and one study reported higher mean haemoglobin levels for the short-stay group at 1 and 3 days postoperatively, but did not adjust for higher preoperative haemoglobin levels in this group [48].
Infection There was low certainty evidence that shortstay programmes may not reduce the odds of infection, No observational studies assessed reoperations, emergency department visits, neurovascular injury, periprosthetic fracture, postoperative falls, dislocation, or stiffness and/or manipulation.

Patient factors
Only one study reported data informing patient selection into short-stay programmes versus usual care [26].This study reported comparable total blood loss for males and females in the short-stay group (p = 0.814), and comparable blood loss per unit body weight (mL/kg) for males and females in the short-stay group (p = 0.97).Four additional studies reported associations between patient factors and safety outcomes [40,66,71,72], but these analyses included all study participants and were not specific to short-stay participants.None of the included studies examined relationships between patient factors and patient-reported pain, function, quality of life or satisfaction outcomes.

Discussion
This systematic review evaluated the safety profile of short-stay programmes for people undergoing elective primary THR or KR, compared to usual care, across four study designs.We examined 14 safety outcomes up to 90 days post-operatively.Only five of these outcomes were included in RCTs, which demonstrated no evidence of harms with respect to hospital readmissions, blood transfusion requirements, other complications, neurovascular injury and stiffness and/or manipulation.However, due to the small number of trials and small number of participants this evidence is of low certainty and at best should be considered as evidence of non-inferiority.While there is some evidence that short-stay joint replacement programmes are cost effective (saving up to $400 [USD] per patient) [14,74], our review shows there are limited head-to-head comparisons with usual care that confirm their safety.The non-RCT studies (registry, interrupted time series and other observational studies) reported inconsistent findings and where benefits were observed (for example, for lower mortality, blood transfusion requirements, other complications, venous thromboembolism (VTE), dislocations and stiffness and/ or manipulation), these results are likely to be overestimated, based on the smaller effect sizes seen with the RCT evidence for the same outcomes.Some safety outcomes have received relatively little attention to date.For example, only one study in our review examined postoperative falls despite an increased risk of this adverse event post-joint replacement surgery [75,76].Falls are an important but commonly overlooked safety outcome, given the potential for both in-hospital and post-discharge falls and sequalae that can include persistent disability or death [77].
We sought to review the evidence underpinning optimal patient selection; however, we identified only one study which reported data relevant to this aim (in relation to blood loss only).None of the included studies examined relationships between clinical or demographic factors and patient-reported pain, function, quality of life or satisfaction outcomes after surgery.This remains an important knowledge gap.One systematic review of patient-reported outcome measures in short-stay orthopaedic surgery in the UK showed that quality of life scores continued to improve up to 12 months postoperatively [78], but data on which patients achieve the greatest improvement is not available.A more recent study comparing short-stay and usual care joint replacement surgery in patients who have experienced both found that satisfaction was higher in the short-stay pathway, but patient-reported outcomes were similar for the two care groups [79].The Enhanced Recovery After Surgery (ERAS ® ) Society recommendations for perioperative joint replacement care are consensusbased (rather than consistently evidence-based) [21] without patient selection specifications, likely due to a lack of high-quality evidence on this aspect.

Strengths and limitations
Strengths of this systematic review include a comprehensive search of the literature across multiple evidence databases, standardised risk of bias appraisal, assessment of evidence certainty and pooled analysis of key safety indicators by study design (both during and after the hospital admission).The results are likely to be broadly generalisable as the included studies were conducted in both middle-and highincome countries and in a variety of healthcare settings including metropolitan and non-metropolitan hospitals, teaching hospitals and military-based hospitals.
In accordance with our review protocol, we did not plan to assess the cost of short-stay programmes, length of stay or adherence to short-stay components in relation to safety or patient outcomes as these aspects have been assessed in previous reviews [14,80,81].We also only examined harms and so the differences between short-stay and usual care participants may have been overestimated where present.As infections and wound complications were inconsistently reported across the included studies, it was not feasible to further categorise these outcomes.We excluded single-group cohort studies but recognise that additional data may be available from this research.Articles published in languages other than English were also excluded from this review (four potentially relevant studies published in Chinese were excluded in the title and abstract screening and fulltext review stages).Based on the similarities of published data in English, we do not anticipate that this would have altered our conclusions.We also note that the review included four studies from China that were published in English, giving representation to short-stay joint replacement research conducted in this country.

Implications for clinical practice
This review has identified that there is insufficient highquality trial evidence to support the 90-day safety profile of short-stay joint replacement programmes compared to usual care.Short-stay programmes may have noninferior safety outcomes (for hospital readmission, blood loss, other complications, neurovascular injury, and stiffness outcomes) compared to usual care, but due to the small number of RCTs, small sample sizes and low event rates, the certainty of this evidence is low.There was no evidence of significant harms (with respect to reoperations, blood transfusion requirements, emergency department visits, infection, mortality, periprosthetic fractures, VTE, wound complications, or dislocation) in the quasi-experimental studies but due to lower levels of evidence we cannot be confident in these findings.Further evidence is required to determine whether shortstay programmes are safer than usual care pathways.This is time critical, given the increasing use of short-stay joint replacement programmes in many international jurisdictions, and the need for evidence-based decisions around resource allocation.
A cluster RCT including different hospital settings (for example, public and private hospitals) could be established to address this important yet unanswered research question.The trial could test a mandated length of stay (for example, 2-3 days) with standardised pre-operative, intra-operative, post-operative and postdischarge multidisciplinary protocols.Efficacy, safety and process outcomes could be evaluated, and the trial would also provide critical (and currently unavailable) data on patient and clinical factors that predict successful discharge home.Efforts to standardise the selection and reporting of safety and patient-related outcomes in short-stay joint replacement research would also facilitate future pooling and analysis of these data.

Conclusions
There is low certainty evidence that short-stay programmes for THR and KR may have non-inferior 90-day safety outcomes, compared to usual care.Most of the included studies used quasi-experimental designs and further evidence from high-quality RCTs is needed to determine whether short-stay programmes are safer than usual care pathways.There remains an important evidence gap around factors associated with poor outcomes, to guide optimal patient selection into short-stay programmes.

Table 1 (
continued) IQR interquartile range, LoS length of stay, SD standard deviation, THR total hip replacement, TKR total knee replacement

Table 2
Short-Stay Programme Components Linked to ERAS Society Recommendations

Table 3
Outcomes included in each study

Table 4
Assessment of Evidence Certainty using GRADEExplanations: a Small event rate from a single study, b Although the RCTs were hampered by an inability to blind the interventions, this does not appear to bias the outcomes

Summary of findings: Short-stay compared to usual care for total hip and knee replacement
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI) CI confidence interval, OR odds ratio GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect